Schizophrenia is a disorder that is characterized by psychosis and pathomorphological brain changes in a significant number of cases. NMDA antagonists (e.g. phencyclidine and ketamine) cause a schizophrenia-like psychosis in humans and pathomorphological changes in corticolimbic neurons of the adult rat. The proposed research focuses on mechanisms by which NMDA antagonists induce these neuronal changes. Specific drugs that suppress drug that suppress the psychotic effects of NMDA antagonists and several drugs that ameliorate psychotic symptoms in schizophrenia, also suppress the neurotoxic effects of NMDA antagonists in the rat cerebral cortex (Olney et al., 1991; Farber et al., 1993a). Onset of susceptibility to NMDA antagonist neurotoxicity in rats does not occur until late adolescence (Farber et al., 1992, 1994b), which is the same age when humans become susceptible to NMDA antagonist-induced psychotic reactions and to schizophrenia. Over the past 18 months the applicant has been working with Dr. Olney in studies that have resulted in the identification of several transmitter systems and receptor subtypes that appear to be involved in this neurotoxic reaction. Over the next five years, the applicant proposes to continue pursuing this research in studies organized around 3 specific aims. Research proposed under the first two aims will provide a better understanding of the complex circuitry underlying the neurotoxic reaction, including which brain regions, transmitter systems and receptor subtypes are involved and where in the circuit specific transmitters interact with specific receptor subtypes. In the third aim the applicant will test a prediction of the proposed circuit, the prediction that by activating specific receptors that putatively serve as proximal mediators of the neurotoxic reaction it will be possible to reproduce the neurotoxicity without administering a NMDA antagonist. An ultimate objective of Aim #3 experiments is to develop a reliable method for reproducing the reaction in vitro as this would facilitate an investigation of intracellular mechanisms that mediate this type of cellular injury. Significance of the proposed research lies in the possibility that it may clarify mechanisms underlying both drug-induced and idiopathic psychotic processes including schizophrenia.